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Invention E-298-2011/1

Pyruvate Kinase M2 Activators for the Treatment of Cancer

Lead Inventor: Craig Thomas (NCATS)
Inventors: Douglas S. Auld (NCATS), Matthew Boxer (NCATS), Jian-kang Jiang (NCATS), Min Shen (NCATS)
Ref. No.: E-298-2011/1

Abstract: This technology describes a series of small-molecule activators of the pyruvate kinase M2 isoform (PK-M2). Pyruvate kinase (PK) is a critical metabolic enzyme that catalyzes the last step of the glycolytic pathway. It exists in several isoforms with different patterns of tissue expression. One isoform, PK-M2, is expressed in cells with a high rate of nucleic acid synthesis, including most tumors, which makes this enzyme an attractive target for cancer therapy. PK-M2 can occur in either a tetrameric form or a dimeric form in proliferating cells; a high tetramer to dimer ratio leads to energy production, while a low ratio channels metabolites into synthetic processes. In tumor cells, oncoproteins induce dimerization of PK-M2, resulting in the inactive form of the protein and allowing synthesis of building blocks for cell proliferation. Activation of PK-M2 in these cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation. Further, after embryonic development PK-M2 expression is primarily restricted to tumor cells, so specific activators of PK-M2 would be expected to affect only tumor cells, and would be less likely to be toxic in normal tissues.


Integrated Phosphoproteomic and Metabolomic Profiling Reveals NPM-ALK-Mediated Phosphorylation of PKM2 and Metabolic Reprogramming in Anaplastic Large Cell LymphomaBlood • Aug. 8, 2013 • NCATS Chemical Genomics Center

Pyruvate Kinase M2 Activators Promote Tetramer Formation and Suppress TumorigenesisNature Chemical Biology • Oct. 2012 • NCATS Chemical Genomics Center

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant ResponsesScience • Dec. 2, 2011 • NCATS Chemical Genomics Center

Evaluation of Thieno[3,2-b]pyrrole[3,2-d]pyridazinones as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate KinaseBioorganic & Medicinal Chemistry Letters • June 1, 2010 • NCATS Chemical Genomics Center

Evaluation of Substituted N,N'-diarylsulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate KinaseJournal of Medicinal Chemistry • Feb. 11, 2010 • NCATS Chemical Genomics Center

Last updated: 07-21-2016
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